Copper is a normal component of the human brain, which contains about 370 mg of copper per gram of tissue ash. This amount of tissue copper ranks second only to that amount found in the liver, the storage organ for copper.
Normal brain development and function requires a number of copper-dependent enzymes. The following is a list of these enzymes and their role in brain function.
______________________________________ Copper-Dependent Enzyme Role in Brain Function ______________________________________ (1) Cyctochrome c oxidase Cellular respiration (2) Cerebrocuprein (cerebral Dismutation of superoxide superoxide dismutase) anion radicals (3) Tyrosinase Conversion of tyrosine to DOPA (4) Dopamine-.beta.-hydroxylase Conversion of dopamine to norepinephrine and epinephrine (5) Lysyl oxidase Conversion of procollagen to tropocollagen and proelastin to elastin in the vasculature ______________________________________
In addition, copper-dependent processes are required for the modulation of prostaglandin syntheses, lysosomal membrane permeability, the activity of histamine, and myelinogenesis.
A variety of brain pathologic disorders accompanied by convulsive seizures are associated with abnormal copper metabolism in humans. Serum copper is elevated in epileptic patients, but brain copper levels are markedly reduced in autopsied epileptics. The elevated serum copper concentrations may indicate physiologic mobilation of copper from the liver to the brain in life but depleted stores leading to copper deficiency may account for decreased brain levels postmortem. Children with severe copper deficiency due to inadequate intake or Menkes' Syndrome, which includes depleted liver copper stores and markedly decreased brain copper levels, are known to have convulsive seizures as a constant feature of their copper deficiency. In addition, neonatal copper deficiency and the copper deficiency associated with Menkes' Syndrome are also associated with severe or terminal central nervous system disorders.
Seizures as well as neuronal and cerebral degeneration also occur in copper-deficient animals. Both quaking mice and mottled mice exhibit tremors as well as neural and central nervous system degeneration as symptoms of their genetic copper deficiency. Rats which are made copper-deficient by removing copper from their diet also exhibit convulsive tremors and central nervous system degeneration. The observation of seizures and central nervous system degeneration in association with a reduction in brain copper levels and concomitant reduction in norepinephrine and epinephrine levels which have been proposed to be seizure modulators, are consistent with known copper requirements [Jobe, P. C., A. L. Picchioni and L. Chin, Role of Brain Norepinephrine in Audiogenic Seizure in the Rat, J. Pharmac. Exp. Ther., 184:1-10 (1973), hereby incorporated by reference]. Further, complexing agents which produce tremors in these animals also reduce brain copper levels [Hadzovic, S., R. Kosak and P. Stern, The Effect of Tremorigenic Substances on the Copper Content of the Rat Brain, J. Neurochem. 3:1027-29 (1966); Price, T. R. and P. Silberfarb, Convulsions Following Disulfiram Treatment, Am. J. Psychiatry, 133:235 (1976), hereby incorporated by reference]. Finally, lambs born to ewes living on copper deficient pastures have a poorly developed central nervous system and exhibit tremors. On recognition, this enzootic ataxia is prevented by injecting the pregnant ewes with copper complexes [Underwood, E. J., In: Trace Elements in Human and Animal Nutrition, 4th Ed. Academic Press, New York, pp. 56-108 (1977), hereby incorporated by reference].
Existing antiepileptic drugs have been found to be ineffective in treating many individuals with epilepsy. This is in part due to serious side effects associated with these agents which include: intolerance, sedation, gingival hyperplasia, ataxia, nystagmus, diplopia, vertigo, psychoses, lethargy, euphoria, mydriasis, headache, hyperactivity, confusion, hallucinations, peripheral neuropathy, gastrointestinal irritation, vomiting, nausea, epigastric pain, anorexia, increased appetite, hypoglycemia, glycosuria, osteomalacia, symptoms of systemic lupus erythematosus, dermatoses, hepatic necrosis, many blood dyscrasias and lymphadenopathy [Woodbury, D. M. and E. Fingl, The Pharmacological Basis of Therapeutics, 5th Ed., MacMillan Pub., New York, pp. 201-225 (1975), hereby incorporated by reference]. Ataxia, anorexia [Underwood, E. J., In: Trace Elements in Human and Animal Nutrition, Id.], peripheral neuropathy, nystagmus, lethargy, and osteomalacia are associated with copper deficiency [Danks, D. M., Copper Transport and Utilization in Menkes' Syndrome and in Mottled Mice, Inorg. Persp. Biol. Med. 1: 73-100 (1977); Sorenson, J. R. J., Therapeutic Uses of Copper, In: Copper in the Environment, Ed. by J. O. Nriagu, John Wiley and Sons, New York, pp. 83-162 (1979); Underwood, E. J., In: Trace Elements in Human and Animal Nutrition, Id., hereby incorporated by reference].